A Bayesian Analysis of the Association Between Leukotriene A4

RESEARCH ARTICLE A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis Laura Whitworth1, Jacob Coxon2, Arjan van Laarhoven3, Nguyen Thuy Thuong Thuong4, Sofiati Dian5,6, Bachti Alisjahbana5, Ahmad Rizal Ganiem5,6, Reinout van Crevel3, Guy E Thwaites4,7, Mark Troll1, Paul H Edelstein1,8, Roger Sewell2*, Lalita Ramakrishnan1* 1Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom; 2Trinity College, Cambridge, United Kingdom; 3Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands; 4Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam; 5Universitas Padjadjaran, TB-HIV Research Center, Faculty of Medicine, Bandung, Indonesia; 6Department of Neurology, Faculty of Medicine/Hasan Sadikin Hospital, Universitas Padjadjaran, Sumedang, Indonesia; 7Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; 8Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States Abstract Tuberculous meningitis has high mortality, linked to excessive inflammation. However, *For correspondence: adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that [email protected] (RS); inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of [email protected] (LR) anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in Competing interests: The the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory authors declare that no eicosanoids. LTA4H TT patients with increased expression had increased survival, consistent with competing interests exist. corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia Funding: See page 14 study did not find an LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H TT genotype confers survival benefit that begins early and Received: 03 August 2020 Accepted: 22 November 2020 continues long-term in both populations. This benefit is nullified in the most severe cases with high Published: 08 January 2021 early mortality. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it. Reviewing editor: Bavesh D Kana, University of the Witwatersrand, South Africa Copyright Whitworth et al. Introduction This article is distributed under Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Despite effective antimicrobial the terms of the Creative ~ Commons Attribution License, therapy, it results in 20–25% mortality in HIV-negative individuals and 40% mortality in HIV-positive which permits unrestricted use individuals (Stadelman et al., 2020; Thwaites et al., 2013). A long-standing hypothesis that an and redistribution provided that excessive intracerebral inflammatory response underlies TBM mortality (Shane and Riley, 1953) led the original author and source are to multiple trials of adjunctive anti-inflammatory treatment with corticosteroids (e.g. dexamethasone) credited. (Prasad et al., 2016; Wilkinson et al., 2017). Findings from a randomised controlled trial (RCT) in Whitworth et al. eLife 2021;10:e61722. DOI: https://doi.org/10.7554/eLife.61722 1 of 40 Research article Genetics and Genomics Microbiology and Infectious Disease eLife digest Tuberculous meningitis is a serious infection of the lining of the brain, which affects over 100,000 people a year. Without treatment, it is always fatal: even with proper antibiotics, about a quarter of patients do not survive and many will have permanent brain damage. Overactive inflammation is thought to contribute to this process. Corticosteroid drugs, which dampen the inflammatory process, are therefore often used during treatment. However, they merely reduce mortality by 30%, suggesting that only some people benefit from them. Two recent studies have linked the genetic makeup of individuals who have tuberculous meningitis to how they respond to corticosteroids. There were, in particular, differences in the LTA4H gene that codes for an inflammation-causing protein. According to these results, only individuals carrying high-inflammation versions of the LTA4H gene would benefit from the treatment. Yet a third study did not find any effect of the genetic background of patients. All three papers used frequentist statistics to draw their conclusions, only examining the percentage of people who survived in each group. Yet, this type of analysis can miss important details. It also does not work well when the number of patients is small, or when the effectiveness of a drug varies during the course of an illness. Another method, called Bayesian statistics, can perform better under these limitations. In particular, it takes into account the probability of an event based on prior knowledge – for instance, that the risk of dying varies smoothly with time. Here, Whitworth et al. used Bayesian statistics to reanalyse the data from these studies, demonstrating that death rates were correlated with the type of LTA4H gene carried by patients. In particular, corticosteroid treatment worked best for people with the high inflammation versions of the gene. However, regardless of genetic background, corticosteroids were not effective if patients were extremely sick before being treated. The work by Whitworth et al. demonstrates the importance of using Bayesian statistics to examine the effectiveness of medical treatments. It could help to design better protocols for tuberculous meningitis treatment, tailored to the genetic makeup of patients. Vietnam that adjunctive dexamethasone improved survival by ~30% led to it becoming standard of care treatment (Thwaites et al., 2004). However, the modest benefit of adjunctive dexamethasone treatment suggested a heterogeneity in glucocorticoid-responsiveness (Donald and Schoeman, 2004; Schoeman and Donald, 2013). Findings in a zebrafish model of TB provided a testable hypothesis for a mechanism underlying this heterogeneity (Thwaites et al., 2004; Tobin et al., 2012; Tobin et al., 2010). The zebrafish findings suggested that either deficiency or excess of leukotriene A4 hydrolase (LTA4H), a key enzyme that regulates the balance of pro- and anti-inflammatory eicosanoids, increase susceptibility to TBM for opposite reasons - too little or too much inflammation (Tobin et al., 2012; Tobin et al., 2010). It became possible to test the prediction when a common human functional LTA4H promoter variant (rs17525495) was identified comprising a C/T transition that controlled LTA4H expression, with the T allele causing increased expression (Tobin et al., 2012). A retrospective analysis of patient LTA4H rs17525495 genotypes in the Vietnam dexamethasone RCT cohort confirmed the prediction (Thwaites et al., 2004; Tobin et al., 2012). Among HIV- negative patients, the survival benefit of dexamethasone was restricted to patients with the hyper- inflammatory TT genotype, with CC patients potentially harmed by this treatment (Tobin et al., 2012). These findings supported the model that mortality from TBM was due to two distinct inflammatory states, and that LTA4H genotype might be a critical determinant of inflammation and conse- quently of the response to adjunctive anti-inflammatory treatment. If true, then personalized genotype-directed adjunctive glucocorticoid treatment would be warranted, with the drug given only to TT patients. This would be particularly important given the possible harm to the hypo-inflammatory CC group, as well as the adverse effects of long-term high dose treatment with a broadly acting immunosuppressant. To further these findings, two new studies of the association of LTA4H genotype with TBM survival in HIV-negative patients were performed in Vietnam and Indonesia, respectively (Thuong et al., 2017; van Laarhoven et al., 2017). Because glucocorticoid adjunctive therapy had become Whitworth et al. eLife 2021;10:e61722. DOI: https://doi.org/10.7554/eLife.61722 2 of 40 Research article Genetics and Genomics Microbiology and Infectious Disease Box 1. Contrast of ‘95% significant’ in Bayesian and frequentist paradigms (MacKay, 2003). Bayes: ‘A is significantly greater than B’ = Posterior probability that A greater than B is at least 0.95. Frequentist: ‘A is significantly greater than B’ = For any circumstance where A is at most B, the probability of getting data in this critical region, as we did, was at most 0.05. Therefore: 1. We expect 1 in 20 of Bayesianly (95%) significant results to be truly negative and therefore false positives; 2. We expect up to 1 in 20 of truly negative results to be frequentistly significant (at the 95% level) and therefore false positives. Therefore (assuming all positives are at 95% level): . In the frequentist paradigm, the expected number of false positive results is proportional to the number of comparisons done on true negatives; . In the Bayesian paradigm, the expected number of false positive results is proportional to the number of apparent positive results, and unaffected by any vast number of accompa- nying apparent negative results. Table 1. Characteristics

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